Most evidence suggests that multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). It is the most common human demyelinating disease. Immune mediated events are involved in the etiology and pathogenesis. Therefore, myelin specific autoreactive T cells are believed to mediate the inflammatory demyelination. In this disease viral infections are associated with initiation and/or exacerbations. Epidemiologic studies indicate that where one lives their first 15 years of life help determines whether one acquires a high or low MS risk phenotype. These data suggest that infections early in life confer a risk or primes individuals for autoimmune disease that originates later in life. Reports show approximately 30% of MS exacerbations (attacks) is preceded by viral infections. While no one infectious agent has been demonstrated to be etiologic agent for MS, there is ample evidence pointing towards viral infections being involved in the initiation and later triggering attacks of disease. We have established an animal model for MS where a viral infection early in life can prime them for exacerbations later in life. The exacerbation is induced by a different viral infection than the first. In our model the first infection has molecular mimicry with a CNS protein(s). We have made a recombinant vaccinia virus (VV) that encodes myelin proteolipid protein (PLP). This initial infection (VV-PLP) does not appear to incite CNS disease by itself. However, when we challenge VV-PLP primed animals with murine cytomegalovirus (MCMV), animals develop inflammatory CNS lesions. The second or challenge infection could induce disease by two mechanisms that are not mutually exclusive: 1) The second infection activates already primed autoreactive T cells by bystander activation, and in sufficient numbers, these T cells would migrate into the CNS and initiate disease; and 2) MCMV could have a cross-reactive epitope with PLP presented by activated dendritic cells to primed autoreactive T cells leading to inflammatory CNS disease. We propose to investigate the immunological basis for the initiation or priming phase and the later challenge phase of inflammatory CNS disease. Our model could provide an explanation why no single microbe has been identified as the MS agent but is likely to be a combination of infectious events.